The long-term objective of this research program is to elucidate the mechanisms of carcinogenesis by nickel compounds. The specific aims of this proposal are: (1) to rank the carcinogenic activities of selected nickel compounds (sulfides, selenides, arsenides, oxides, antimonide, titanide, ferronickel alloy, and nickel metal) after administration to Fischer rats by intramuscular (im) and intrarenal (ir) routes, (2) to evaluate correlations between the carcinogenic activities of the nickel compounds and (a) solubilities in biological fluids, (b) susceptibilities to phagocytosis by rat macrophages, c) capabilities to induce erythrocytosis after ir injection in rats, and (d) potencies as inducers of heme oxygenase activity in rat kidney microsomes; (3) to elucidate the inhibitory effect of manganese upon the carcinogenecity and other biological effects of nickel compounds, and (4) to develop new experimental models for study of nickel carcinogenesis. The current methods include (1) carcinogenesis testing in rats and guinea pigs, (2) histological and electron microscopic investigations of pathological lesions in rats during induction of renal cancers by alpha Ni3S2; (3) bioassays of erythropoietin activity in serum and renal homatogenesis of alpha Ni3S2-treated rats, (4) chromatographic and electrophoretic fractionations of 63Ni-bound to macromolecules in tissue homogenates of 63Ni-treated rats; and (5) gas chromatographic assays of heme oxygenase activity in rat kidney microsomes after adminstration of nickel compounds. This study is providing fundamental knowledge of nickel carcinogenesis, and is also furnishing information with practical applications to assessing human hazards of carcinogenesis from nickel compounds, with particular relevance to industrial toxicology, environmental pollution, and energy production.